It has been well established that T-cells play an important role in regulating immune response (F. Powrie and R. L. Coffman, Immunol. Today, 1993, 14, 270). Indeed, activation of T-cells is often the initiating event in many inflammatory and autoimmune diseases. IL-2 is an autocrine growth factor which plays an essential role in the regulation of T-cell activation and proliferation. Clinical studies have shown that interference with IL-2 activity effectively suppresses immune response in vivo (T. A. Waldmann, Immunol. Today, 1993, 14, 264). Accordingly, agents which inhibit IL-2 production are therapeutically useful for selectively suppressing immune response in a patient in need of such immunosuppression.
Previously, others have attempted to interfere with the activity of IL-2 by using cytokine antagonists, monoclonal antibodies, toxins and other biologics which seek to prevent IL-2 from binding to its receptor (G. Mazur and I. Frydecka, Acta Haematol. Pol., 1993, 24, 307). More recently, others have attempted to inhibit IL-2 production at the T-cell level, for example by blocking the expression of IL-2 mRNA with glucocorticoids or cyclosporin A. However, to date, the reported compounds suffer from several disadvantages such as low potency, poor in vivo activity, toxicity and poor oral bioavailability. Accordingly, a need exists for compounds that can effectively inhibit IL-2 production for preventing and treating immune disorders.
U.S. application Ser. No. 09/324,933 discloses substituted 1-(4-aminophenyl)pyrazoles as anti-inflammatory agents. WO9919303 describes substituted phenyl-, heteroaryl- and heterocyclyl-substituted pyrazoles as useful in the treatment of allergy, inflammatory and autoimmune diseases. WO9951580 describes substituted pyrazoles as inhibitors of cytokine production.
The compounds of this invention are 1-(4-aminophenyl)imidazoles optionally substituted on the imidazole ring and on the amino group on the 4-position of the phenyl ring, having antiinflammatory activity by virtue of their ability to inhibit IL-2 production in T-lymphocytes.
In its broadest generic aspect, the invention comprises 1-(4-aminophenyl)imidazoles of Formulas Ia and Ib 
wherein:
R1 and R2, which may be the same or different, are CF3; halogen; CN; branched or unbranched C1-8 alkyl; branched or unbranched C1-8 alkenyl; C3-8 cycloalkyl optionally substituted with OH, CN or methoxy; C1-8 alkoxy; C1-4 alkyloxyalkyl; C1-8 alkylthio; C1-4 alkylthioalkyl; C1-8 dialkylamino; C1-4 dialkylaminoalkyl; CO2R4 where R4 is C1-4 alkyl or C1-4 alkenyl optionally substituted with carbocyclyl or heterocyclyl; aryl or heterocyclyl connected to the imidazole in any position that makes a stable bond which aryl or heterocyclyl may be optionally substituted with halogen, C1-4 alkyl, C1-4 alkenyl, CN, Me2N, CO2Me, OMe, aryl, heterocyclyl or R4;
L is xe2x80x94NHC(O)xe2x80x94; xe2x80x94NHC(O)Oxe2x80x94; xe2x80x94NHC(O)C(O)xe2x80x94; xe2x80x94NHC(S)xe2x80x94; xe2x80x94NHxe2x80x94; xe2x80x94NHC(O)NHxe2x80x94; xe2x80x94NHC(S)NHxe2x80x94; xe2x80x94NHCHxe2x80x942; xe2x80x94NHCH(R5)xe2x80x94 where R5 is H, CN, C1-6 alkyl, C1-6 alkyloxyoalkyl C1-6 alkythioalkyl, C1-6 alkylsulfinylalkyl, C1-6 alkysulfonylalkyl, C3-6 cycloalkyl, heterocyclyl or aryl optionally substituted with a halogen, C1-4 alkyl, CN, Me2N, CO2Me or OMe; or L is xe2x80x94NHC(R5)-lower alkyl;
R3 is C1-8 alkyl; C1-8 alkyloxy; C1-8 alkylthio; C1-8 alkylamino; C1-4 alkoxyalkyl; C1-4 alkylthioalkyl; C1-4 alkylaminoalkyl; C1-4 dialkylalkylaminoalkyl; carbocyclyl or heterocyclyl, which carbocyclyl or heterocyclyl may optionally be substituted with one or more of the following: halogen, xe2x80x94CN, xe2x80x94NO2, xe2x80x94SO2NH2 or R6 (where R6 is phenyl, heterocyclyl, C3-6-cycloalkyl, C1-6-alkyl, C2-6-alkenyl, C1-6-alkyloxyalkyl, C1-6-alkylthioalkyl, C1-6-alkylsulfinylalkyl, C1-6-alkylsulfonylalkyl or C2-6-alkynyl) and R6 may be optionally substituted with halogen, xe2x80x94OH, alkyloxy, xe2x80x94CN, xe2x80x94COO-lower alkyl, xe2x80x94CONH-lower alkyl, xe2x80x94CON (lower alkyl)2, dialkylamino, phenyl or heterocylcyl; or R3 is xe2x80x94CO2R6; xe2x80x94N(R2); xe2x80x94NH(R6); xe2x80x94C(O)R6; xe2x80x94OR6; S(O)nR6 where n is O, 1 or 2; xe2x80x94SO2NHR6; or xe2x80x94SO2N(R6)2; or a pharmaceutically acceptable derivative thereof.
In order that the invention herein described may be more fully understood, the following detailed description is set forth. As used herein, the following abbreviations are used:
DMAP is 4-dimethylamino pyridine;
DMF is dimethylformamide;
DMSO is dimethylsulfoxide;
Et is ethyl;
EtOAc is ethyl acetate;
Me is methyl;
MeOH is methanol; and
EDC is 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride.
Also, as used herein, each of the following terms, used alone or in conjunction with other terms, are defined as follows (except where noted to the contrary):
The term xe2x80x9calkylxe2x80x9d refers to a saturated aliphatic radical containing from one to ten carbon atoms. xe2x80x9cAlkylxe2x80x9d refers to both branched and unbranched alkyl groups. Preferred alkyl groups are straight chain alkyl groups containing from one to eight carbon atoms and branched alkyl groups containing from three to eight carbon atoms. More preferred alkyl groups are straight chain alkyl groups containing from one to six carbon atoms and branched alkyl groups containing from three to six carbon atoms. xe2x80x9cAlkylxe2x80x9d, as used herein, includes unsubstituted alkyl radicals, those radicals that are partially or fully halogenated and those radicals substituted with one to four, preferably one or two, substituents selected from amino, cyano, nitro, methoxy, ethoxy and hydroxy. The term xe2x80x9ccycloalkylxe2x80x9d refers to the cyclic analog of an alkyl group, as defined above. Preferred cycloalkyl groups are saturated cycloalkyl groups containing from three to eight carbon atoms, and more preferably three to six carbon atoms. xe2x80x9cAlkylxe2x80x9d and xe2x80x9ccycloalkylxe2x80x9d, as used herein, include unsubstituted alkyl and cycloalkyl radicals, those radicals that are partially or fully halogenated and those radicals substituted with one to four, preferably one or two, substituents selected from halo, amino, cyano, nitro, methoxy, ethoxy and hydroxy. It should be understood that any combination term using an xe2x80x9calkxe2x80x9d or xe2x80x9calkylxe2x80x9d prefix refers to analogs according to the above definition of xe2x80x9calkylxe2x80x9d. For example, terms such as xe2x80x9calkoxyxe2x80x9d, xe2x80x9calkythioxe2x80x9d refer to alkyl groups linked to a second group via an oxygen or sulfur atom.
The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d refer to a mono- or polyunsaturated aliphatic hydrocarbon radical containing from two to twelve carbon atoms, containing at least one double or triple bond, respectively. xe2x80x9cAlkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d refer to both branched and unbranched alkenyl and alkynyl groups. Preferred alkenyl and alkynyl groups are straight chain alkenyl or alkynyl groups containing from two to eight carbon atoms and branched alkenyl or alkynyl groups containing from five to ten carbon atoms. More preferred alkenyl and alkynyl groups are straight chain alkenyl or alkynyl groups containing from two to six carbon atoms and branched alkenyl or alkynyl groups containing from five to eight carbon atoms. xe2x80x9cAlkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d, as used herein, include unsubstituted alkenyl or alkynyl radicals, those radicals that are partially or fully halogenated and those radicals substituted with one to four, preferably one or two, substituents selected from halo, amino, cyano, nitro, methoxy, ethoxy and hydroxy.
The term xe2x80x9carylxe2x80x9d refers to phenyl and naphthyl, phenyl and naphthyl that are partially or fully halogenated and phenyl and naphthyl substituted with halo, alkyl, hydroxy, nitro, xe2x80x94COOH, xe2x80x94CO(lower alkoxy), xe2x80x94CO(lower alkyl), amino, alkylamino, dialkylamino, alkoxy, xe2x80x94NCOH, xe2x80x94NCO(lower alkyl), xe2x80x94NSO2-Ph(halo)0-3, Ph, xe2x80x94O-Ph; naphthyl, xe2x80x94O-naphthyl, pyrrolyl, pyrrolyl substituted with lower alkyl, pyridyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl.
The term xe2x80x9chaloxe2x80x9d refers to a halogen radical selected from fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term xe2x80x9ccarbocyclylxe2x80x9d refers to a stable 3-8 membered (but preferably, 5 or 6 membered) monocyclic or 7-11 membered bicyclic radical which may be either saturated or unsaturated, aromatic or non-aromatic. Preferred carbocycles include, for example, phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, indanyl, indenyl, dihydronaphthyl and tetrahydronaphthyl. Most preferred heterocycles of this invention are phenyl, naphthyl, cyclohexyl, tetrahydronaphthyl and indanyl. xe2x80x9cCarbocyclylxe2x80x9d refers to unsubstituted carbocyclic radicals, those radicals that are partially or fully halogenated and those radicals substituted with alkyl; hydroxyl; nitro; xe2x80x94COOH; xe2x80x94CO(lower alkoxy); xe2x80x94CO(lower alkyl); amino; alkylamino; dialkylamino; alkoxy; xe2x80x94NCHO; xe2x80x94NCO(lower alkyl); xe2x80x94NSO2-Ph(halo)0-3, Ph; xe2x80x94O-Ph; naphthyl; xe2x80x94O-naphthyl; pyrrolyl; pyrrolyl substituted with lower alkyl; pyridyl; pyridinyl; pyrazinyl; pyrimidinyl and pyridazinyl.
The term xe2x80x9cheterocyclexe2x80x9d refers to a stable 5-8 membered (but preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic heterocycle radical which may be either saturated or unsaturated, aromatic or non-aromatic, and which may be optionally benzo- or pyridofused if monocyclic. Each heterocycle consists of carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. As used herein, xe2x80x9cnitrogenxe2x80x9d and xe2x80x9csulfurxe2x80x9d include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen. The heterocycle may be attached by any atom of the cycle, which results in the creation of a stable structure. Preferred heterocycles include, for example, benzimidazolyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, quinolinyl, isoquinolinyl, indolyl, oxazolyl, pyridyl, pyrrolyl, pyrrolinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinoxolyl, piperidinyl, morpholinyl, thiomorpholinyl, furyl, thienyl, triazolyl, thiazolyl, xcex2-carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiomorpholinyl sulfone, benzoxazolyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, isoxazolyl, tetrahydropyranyl, tetrahydrofuranyl, thiadiazoyl, benzodioxolyl, tetrahydrothiophenyl and sulfolanyl. Most preferred heterocycles of this invention include imidazolyl, pyridyl, pyrrolyl, pyrazolyl, piperidinyl, morpholinyl, furyl, thienyl, thiazolyl and the benzo- and pyrido-fused derivatives thereof. xe2x80x9cHeterocyclylxe2x80x9d refers to unsubstituted heterocycle radicals, those radicals that are partially or fully halogenated and those radicals substituted with alkyl, hydroxyl, nitro, xe2x80x94COOH, xe2x80x94CO(lower alkoxy), xe2x80x94CO(lower alkyl), amino, alkylamino, dialkylamino, alkoxy, xe2x80x94NCHO, xe2x80x94NCO(lower alkyl), xe2x80x94NSO2-Ph(halo)0-3, Ph, xe2x80x94O-Ph, naphthyl, xe2x80x94O-naphthyl, pyrrolyl, pyrrolyl substituted with lower alkyl, pyridyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl.
The term xe2x80x9clowerxe2x80x9d used in conjunction with other terms (e.g., xe2x80x9calkylxe2x80x9d, xe2x80x9calkoxyxe2x80x9d and the like) refers to a radical containing from one to six, preferably from one to five and more preferably, from one to four carbon atoms. For example, a xe2x80x9clower alkylxe2x80x9d group is a branched or unbranched alkyl radical containing from one to six carbon atoms.
The term xe2x80x9cpatientxe2x80x9d refers to a warm-blooded animal, and preferably a human.
The term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d or xe2x80x9cpharmaceutically acceptable adjuvantxe2x80x9d refers to a non-toxic carrier or adjuvant that may be administered to a patient together with a compound of this invention and which does not destroy the pharmacological activity of that compound.
It should be understood that any compounds of this invention containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic center may be in the R or S configuration, or a combination of configurations.
The compounds of this invention are defined to include pharmaceutically acceptable derivatives thereof. A xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d refers to any pharmaceutically acceptable salt, ester, or salt of an ester of a compound of this invention, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound of this invention, a pharmacologically active metabolite or pharmacologically active residue thereof.
Combinations of substituents and variables encompassed by this invention are only those that result in the formation of stable compounds. The term xe2x80x9cstablexe2x80x9d as used herein, refers to compounds which possess stability sufficient to permit manufacture and administration to a patient by conventional methods known in the art. Typically, such compounds are stable at a temperature of 40xc2x0 C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
The compounds of this invention may be used in the form of salts derived from inorganic or organic acids. Included among such acid salts, for example, are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, tosylate and undecanoate.
This invention relates to substituted 1-(4-aminophenyl)imidazoles and analogs thereof that inhibit interleukin-2 (IL-2) production. In one embodiment, this invention relates to a novel class of substituted 1-(4-aminophenyl)imidazoles and pharmaceutical compositions comprising these compounds. Because of their selective immunomodulating properties, the compounds and pharmaceutical compositions of this invention are particularly well suited for preventing and treating immune disorders, including autoimmune disease, inflammatory disease, organ transplant rejection and other disorders associated with IL-2 mediated immune response.
The substituted 1-(4-aminophenyl)imidazoles of this invention are represented by Formulas Ia and Ib 
wherein:
R1 and R2, which may be the same or different, are CF3; halogen; CN; branched or unbranched C1-8 alkyl; branched or unbranched C1-8 alkenyl; C3-8 cycloalkyl optionally substituted with OH, CN or methoxy; C1-8 alkoxy; C1-4 alkyloxyalkyl; C1-8 alkylthio; C1-4 alkylthioalkyl; C1-8 dialkylamino; C1-4 dialkylaminoalkyl; CO2R4 where R4 is C1-4 alkyl or C1-4 alkenyl optionally substituted with carbocyclyl or heterocyclyl; aryl or heterocyclyl connected to the imidazole in any position that makes a stable bond which aryl or heterocyclyl may be optionally substituted with halogen, C1-4 alkyl, C1-4 alkenyl, CN, Me2N, CO2Me, OMe, aryl, heterocyclyl or R4;
L is xe2x80x94NHC(O)xe2x80x94; xe2x80x94NHC(O)Oxe2x80x94; xe2x80x94NHC(O)C(O)xe2x80x94; xe2x80x94NHC(S)xe2x80x94; xe2x80x94NHxe2x80x94; xe2x80x94NHC(O)NHxe2x80x94; xe2x80x94NHC(S)NHxe2x80x94; xe2x80x94NHCHxe2x80x942; xe2x80x94NHCH(R5)xe2x80x94 where R5 is H, CN, C1-6 alkyl, C1-6 alkyloxyoalkyl C1-6 alkythioalkyl, C1-6 alkylsulfinylalkyl, C1-6 alkysulfonylalkyl, C3-6 cycloalkyl, heterocyclyl or aryl optionally substituted with a halogen, C1-4 alkyl, CN, Me2N, CO2Me or OMe; or L is xe2x80x94NHC(R5)-lower alkyl;
R3 is C1-8 alkyl; C1-8 alkyloxy; C1-8 alkylthio; C1-8 alkylamino; C1-4 alkoxyalkyl; C1-4 alkylthioalkyl; C1-4 alkylaminoalkyl C1-4 dialkylalkylaminoalkyl; carbocyclyl or heterocyclyl, which carbocyclyl or heterocyclyl may optionally be substituted with one or more of the following:
halogen, xe2x80x94CN, xe2x80x94NO2, xe2x80x94SO2NH2 or R6 (where R6 is phenyl, heterocyclyl, C3-6 cycloalkyl, C1-6 alkyl, C2-6 alkenyl, C1-6 alkyloxyalkyl, C1-6 alkylthioalkyl, C1-6 alkylsulfinylalkyl, C1-6 alkylsulfonylalkyl or C2-6 alkynyl) and R6 may be optionally substituted with halogen, xe2x80x94OH, alkyloxy, xe2x80x94CN, xe2x80x94COO-lower alkyl, xe2x80x94CONH-lower alkyl, xe2x80x94CON(lower alkyl)2, dialkylamino, phenyl or heterocylcyl; or R3 is xe2x80x94CO2R6; xe2x80x94N(R6)2; xe2x80x94NH(R6); xe2x80x94C(O)R6; xe2x80x94OR6; S(O)nR6 where n is O, 1 or 2; xe2x80x94SO2NHR6; or xe2x80x94SO2N(R6)2; or a pharmaceutically acceptable derivative thereof.
Preferably, the novel substituted 1-(4-aminophenyl)imidazoles of Formula Ia or Ib are those wherein:
R1 is straight-chained, branched or cyclo-C3-8alkyl, alkenyl, or alkynyl; C1-3alkyloxyalkyl, C1-5 alkyloxy, C1-3alkylthioalkyl, C1-5alkylthio, CF3; heterocyclyl or aryl optionally substituted with halogen, C1-4alkyl, CN, alkoxy or Me2N;
R2 is halogen, Me, Et, CF3, CN, cyclopropyl, vinyl, SMe, OMe, heterocyclyl or aryl optionally substituted with halogen, C1-4 alkyl, CN, alkoxy or Me2N;
L is xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NHC(O)NH, or xe2x80x94NHCH(R5)xe2x80x94, where R5 is H, C1-4 alkyl, or CN and
R3 is C1-6 alkyl, C1-4 alkyloxyalkyl, C1-4 alkylthioalkyl, cyclohexyl, cyclopentyl, indanyl, indolyl, phenyl, thienyl, naphthyl, isoxazolyl or pyridyl, optionally substituted with one or more halogen, xe2x80x94CN, xe2x80x94NO2, SO2NH2, or R6 where R6 is C1-6 alkyl, C2-6 alkenyl, C1-6 alkyloxyalkyl, C1-6 alkylthioalkyl, or C2-6 alkynyl, optionally substituted with OH, CN, xe2x80x94COO-lower alkyl, xe2x80x94CONH-lower alkyl, xe2x80x94CON(lower alkyl)2, dialkylamino, or heterocycyl, CO2R6, xe2x80x94N(R6)2, xe2x80x94NH(R6), xe2x80x94C(O)R6, xe2x80x94OR6, S(O)nR6 where n is 0, 1 or 2, xe2x80x94SO2NHR6, xe2x80x94SO2N(R6)2.
More preferred are novel substituted 1-(4-aminophenyl)imidazoles of Formula Ia or Ib wherein:
R1 is Et, i-Pr, n-Pr, t-Bu, cyclopentyl, CF3, xe2x80x94OEt, MeOCH2xe2x80x94, 2- or 3-tetrahydrofuranyl, 2-, 3-, or 4-pyridyl, 2-furanyl, or 2-thiazolyl;
R2 is CN, CF3, Cl, Me, Et, SMe, cyclopropyl, vinyl, or 2-furanyl;
L is xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94NHCH2xe2x80x94; and
R3 is a phenyl ring which is optionally substituted with one to three groups selected from C1-3alkyl, chloro, fluoro, CF3, OC1-4alkyl, OC3-5alkenyl, CO2C1-2alkyl, SMe, CN, NO2, NMe2 and O(CH2)pR7, where p is 3 or 4 and R7 is CN, CO2Me, 2-(1,3-dioxolanyl), OH, or OC6H5; 1- or 2-indanyl, 2-tetrahydropyranyl, or a heterocycle selected from the group consisting of 2-thienyl, 3-furanyl, 3- or 4-pyridyl, 4-isoxazolyl, 1-isoquinolinyl, 2-indolyl, 2-benzothienyl and 4-pyrazolyl, which may be optionally substituted with one to three groups selected from Cl, Br, Me, CN, CF3, OCF3, NO2, or O(CH2)pR7, where p is 3 or 4 and R7 is CN, CO2Me, 2-(1,3-dioxolanyl), OH, or OC6H5; C5-6 alkyl, C5-6cycloalkyl, or cyclohexenyl.
Especially preferred are novel substituted 1-(4-aminophenyl)imidazoles of Formula Ia or Ib wherein:
R1 is i-Pr, CF3, 3-pyridyl or 4-pyridyl;
R2 is CN, CF3, Cl, Me, SMe or Et;
L is xe2x80x94NHC(O)xe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94NHCH2xe2x80x94; and
R3 is a phenyl ring which is optionally substituted with O(CH2)3R8, where R8 is CN, OH or 2-(1,3-dioxolanyl); OC3-4alkyl, O(CH2)4OH, 1-pentenyl, one to three groups selected from Me, Cl, F and CN; 3-pyridyl optionally substituted in the 6-position with O(CH2)2OEt or O(CH2)3R8, where R8 is CN, OH or 2-(1,3-dioxolanyl); 4-pyridinyl optionally substituted with a chlorine, 2-thienyl optionally substituted with Me or Br, 3,5-dimethyl-4-isoxazolyl, 1-methyl-2-indolyl, cyclopentyl, cyclohexyl, 1-indanyl or n-pent-3-yl.
Compounds of Formula Ia or Ib in which L is xe2x80x94NHC(O)xe2x80x94 may be prepared by one of the methods outlined below. For example, a (4-aminophenyl) disubstituted imidazole 1a or 1b may be reacted with a carboxylic acid 2 under suitable coupling conditions known to one skilled in the art, for example in the presence of EDC and a base catalyst such as N,N-dimethylaminopyridine in a suitable solvent such as methylene chloride acetonitrile or DMF (Method A). Alternatively, 1a or 1b could be coupled with an acid halide 3 in the presence of a suitable base such as triethylamine in a suitable solvent such as methylene chloride (Method B). 
Compounds of Formula Ia or Ib in which L is xe2x80x94NHxe2x80x94 and R3 is a heteroaryl ring may be prepared, as illustrated below, by reaction of 1a or 1b with a heterocycle 4 containing a labile substituent such as a halogen, which may be displaced by nucleophilic substitution (Method C). The reaction may be carried out in a sealed tube or an open vessel, at ambient temperature or heated to 150xc2x0 C. in a suitable solvent such as dioxane or THF. A base such as sodium bis-trimethylsilyl amide may be added to the reaction. 
Compounds in which L is xe2x80x94NHC(O)NHxe2x80x94 may be prepared by reaction of isocyanate 5a or 5b with an amine 6 in a suitable solvent such as methylene chloride or toluene (Method D). An amine such as triethylamine may be added. Alternatively, 1a or 1b could be reacted with an amine carbonyl chloride such as N-morpholine carbonyl chloride 7 in a suitable solvent such as methylene chloride (Method E). Intermediates 5a and 5b may be prepared from 1a and 1b, respectively, by methods known to those skilled in the art, for example by reaction of 1a or 1b with phosgene or a phosgene equivalent in the presence of a suitable base such as potassium carbonate, in a suitable solvent, such as methylene chloride. 
Methods by which compounds in which L is xe2x80x94NHCH(R5)xe2x80x94 or xe2x80x94NHCH2 may be prepared are illustrated below. The procedures are illustrated for Ia, but may be used for Ib as well by substituting the appropriate starting material. For example, these compounds may be prepared by reduction of the corresponding amide (Ia or Ib, L is xe2x80x94NHC(O)xe2x80x94) with a suitable reducing agent such as lithium aluminum hydride, in a suitable solvent such as THF or diethyl ether (Method F). Alternatively, amine 1a or 1b could react with an alkylating agent 8 (Method G) where X is a suitable leaving group such as a halogen. In another alternate procedure, amine 1a or 1b could react with an aldehyde 9, and the intermediate imine 10 reacted with a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride (Method I). Alternatively, 10 could be reacted with a nucleophile such as an alkyl or aryl lithium reagent (Method I). 
Intermediates useful in the synthesis of compounds of formula Ia may be prepared as described below. A 3,5-disubstituted imidazole may be reacted with nitrobenzene substituted in the 4-position with a leaving group such as a halogen in the presence of a base (Method J). The nitrophenylimidazoles (11) produced could then be reduced to aminophenyl imidazoles by using a reducing agent such as SnCl2 or hydrogen or a hydrogen source such as ammonium formate in the presence of a catalyst such as palladium. Desired 3,5-disubstituted imidazoles may be prepared by methods known to those skilled in the art, such as by reaction of an alpha-bromoketone (R1C(O)CH2Br) with an amidine (R2C(xe2x95x90NH)NH2) (for example, see T. L. Little and S. E. Webber, J. Org Chem., 1994, 59, 7299). 
Intermediates 1a, in which R1 is CF3, useful in several of the Methods described above, may be prepared using a general procedure described in the chemical literature (M. Kawase et al., Heterocycles, 1995, 41, 1617) and illustrated by Method K below. 
In this procedure, a protected glycine, such as glycine t-butyl ester, is reacted with a 4-halonitrobenzene, such as 4-fluoronitrobenzene, in the presence of a suitable base, such as potassium carbonate, to provide 12, This is acylated with an acyl chloride R2C(O)Cl, to provide 13. Removal of the t-butyl ester by reaction with a suitable acid such as trifluoroacetic acid, is followed treatment with trifluoroacetic anhydride resulting in cyclization to mesoionic species 14. Treatment with ammonium acetate provides 15, which under suitable dehydration conditions, for example treatment with POCl3 in pyridine, provides imidazole 16. This may then be reduced as described above (Method J) to the desired 1a (R1=CF3).
Method K may be adapted to prepare compounds of the invention with other R1. By substituting an acid chloride (R1C(O)Cl) or acid anhydride (R1C(O)OC(O)R1) and a suitable base, such as dimethylaminopyridine, for trifluoroacetic anhydride in the conversion of 13 to 14 above, one may obtain 14a with the desired R1. This may then be converted to the desired 1a as described in Method K. 
By altering the positions of the substituents, Method K may be modified to produce compounds of formula Ib as illustrated by Method Kxe2x80x2. In this procedure, an N-substituted glycine ester, such as the methyl ester shown below is reacted with 4-nitrobenzoyl chloride in a suitable solvent such as methylene chloride or THF, in the presence of a suitable base, such as triethylamine or N-methylmorpholine to provide 17. Hydrolysis, followed by treatment with an acid chloride or acid anhydride, in a fashion analogous to the conversion of 13 to 14a, provides 18. This is then converted to the desired intermediate 1b as described for the conversion of 14 to 1a in Method K. 
Method L illustrates another procedure by which 2-cyanoimidazoles may be obtained. A suitably protected substituted imidazole, where the protecting group P is trityl for example, may be reacted with a strong base, such as n-butyl lithium, and the resulting anion reacted with ethyl chloroformate to give the ethyl ester. Deprotection may be followed by reaction with nitrofluorobenzene (Method J) to give the nitrophenyl imidazole ester. The ester may then be converted to the nitrile by methods known to those skilled in the art, for example by conversion to the amide and dehydration as illustrated below. 
Several additional intermediates useful for the synthesis of compounds of formula Ia could be obtained from the 5-bromoimidazole 17, which may be prepared by bromination of the corresponding R1-substituted nitrophenylimidazole. For example, as illustrated in Method M, 17 may be cross coupled with a terminal acetylene 18, where Z may be, for example, hydrogen, or an alkyl group or any other group not adversely affecting the reaction, using conditions described by T. Sakamoto et al., (Synthesis, 1983, 312) to provide an alkyne at R2 (19). Alternatively, reaction with vinylstannanes 20, Z defined as above, under conditions described by J. W. Stille (Angew. Chem. Int. Ed. Engl., 1986, 25, 508), provides an alkene at R2 (21) (Method N). Reaction with substituted or unsubstituted aryl- or heteroarylboronic acids (22) under conditions described by N. Miyaura et al. (Chem. Rev. 1995, 95, 2457) provides 23 with aryl or heteroaryl groups at R2 (Method O). Alkynes 19 and alkenes 21 may be converted to the corresponding alkyl groups by reduction with a suitable reducing agent such as hydrogen in the presence of a suitable catalyst such as platinum or palladium to provide 1a (see Method J), with an alkyl group at R2. Alternatively, reaction with a reducing agent that leaves alkenes and alkynes intact, such as SnCl2 provides 1a with alkenes or alkynes at R2. 
Method P describes an alternate procedure for preparing compounds of Formula Ia or Ib where L is xe2x80x94NHxe2x80x94. As illustrated in below, intermediate 1a may be heated at about 70xc2x0 C. with an aryl bromide in the presence of a palladium catalyst, preferably Pd2(dba)3, 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binapthyl (BINAP), and a base, preferably NaOt-Bu, in a solvent such as toluene, as described by S. Buchwald et al. (J. Amer. Chem. Soc., 1993, 119, 8451) to provide Ia (L=xe2x80x94NHxe2x80x94). Using the same Method and starting with intermediate 1b would provide Ib (L=xe2x80x94NHxe2x80x94). Alternately, one could employ the same conditions with the bromophenylimidazole 24 and an amine, R3NH2, as illustrated for Ia below. 
As can be appreciated by chemists possessing ordinary skill in the art, the synthetic schemes described above are for illustrative purposes only and may be modified using conventional synthetic methodology to produce any of the analogs of Formula I. Depending on precisely how the synthetic schemes are modified, the specific reaction conditions might also require modification. Such modifications may involve the use of higher or lower temperature or pressure, conditions other than those reported herein, or the addition of further synthetic steps such as functional group transformations. However, since progress of the reactions is easily monitored by techniques such as high performance liquid chromatography, gas chromatography, mass spectroscopy, thin layer chromatography, nuclear magnetic resonance spectroscopy and the like, such modifications are well within the skill of the art. Likewise, it should be appreciated that initial products from these Methods could be further modified to make additional compounds of this invention. Intermediates used in the Methods described above may be commercially available or could be prepared from commercially available materials by methods described in the chemical literature and known to people skilled in the art.
The 1-phenylimidazole analogs of Formula Ia and Ib inhibit production of IL-2. Without wishing to be bound by theory, the compounds of this invention inhibit IL-2 production by T-cells. This inhibition of IL-2production is therapeutically useful for selectively suppressing immune function. The result of such selectively suppressed immunity includes reduced cell proliferation of peripheral blood lymphocytes and cellular immune response. Thus, the inhibition of IL-2 production is an attractive means for preventing and treating a variety of immune disorders, including inflammatory diseases, autoimmune diseases, organ and bone marrow transplant rejection and other disorders associated with IL-2 mediated immune response. In particular, the compounds of Formula I may be used to prevent or treat acute or chronic inflammation, allergies, contact dermatitis, psoriasis, rheumatoid arthritis, multiple sclerosis, type 1 diabetes, inflammatory bowel disease, Guillain-Barre syndrome, Crohn""s disease, ulcerative colitis, graft versus host disease (and other forms of organ or bone marrow transplant rejection) and lupus erythematosus. Other disorders associated with IL-2 mediated immune response will be evident to those of ordinary skill in the art and can also be treated with the compounds and compositions of this invention.
The compounds of this invention may be administered in any conventional dosage form in any conventional manner. Such methods of treatment, including their dosage levels and other requirements, may be selected by those of ordinary skill in the art from available methods and techniques. For example, a compound of this invention may be combined with a pharmaceutically acceptable carrier or adjuvant for administration to a patient in need of such treatment in a pharmaceutically acceptable manner and in an amount effective to treat (including lessening the severity of symptoms) the immune disorder.
The compounds of this invention may be administered alone or in combination with conventional therapeutics, such as conventional immunosuppressants. Advantageously, such combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies. The compounds of this invention may be physically combined with the conventional therapeutics into a single pharmaceutical composition. Advantageously, the compounds may then be administered together in a single dosage form. Alternatively, the compounds may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regime.
According to this invention, the compounds of Formula Ia and Ib and the pharmaceutical compositions containing those compounds may be administered to a patient in any conventional manner and in any pharmaceutically acceptable dosage from, including, but not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by infusion, sublingually, transdermally, orally, topically or by inhalation. The preferred modes of administration are oral and intravenous.
Dosage forms of the compounds of this invention include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances. Preferred dosage forms include tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch. Methods for preparing such dosage forms are known (see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger, 1990). Dosage levels and requirements are well-recognized in the art and may be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. Typically, dosage levels range from about 10-1000 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be given. For oral doses, up to 5000 mg/day may be required. As the skilled artisan will appreciate, lower or higher doses may be required depending on particular factors. For instance, specific dosage and treatment regimens will depend on factors such as the patient""s general health profile, the severity and course of the patient""s disorder or disposition thereto and the judgment of the treating physician.
Synthetic Examples